Liver plays an important role of metabolizing exogenous and endogenous substances in human body. When liver tissues are continuously exposed to frequent alcoholic drinking or crapulence, viral infection or drug misuse and abuse, the liver tissues are easily damaged and subsequently develop into chronic liver diseases such as hepatic fibrosis and liver cirrhosis. Since hepatic fibrosis does not show any pain or a particular symptom until it is discovered at a terminal stage, its death rate is relatively high and thus its development often becomes a social problem.
In particular, liver disease can be divided into several procedural symptoms. The damaged tissues are first converted into fatty liver in its early stage and then developed into hepatitis, and finally into hepatic fibrosis and liver cirrhosis. Generally, it has been reported that the progress up to hepatic fibrosis is reversible, but once it is developed into liver cirrhosis, its subsequent process becomes irreversible. Accordingly, liver disease can be cured by administering a drug at a stage prior to the development of hepatic fibrosis or an early fibrosis stage.
Liver cirrhosis is caused by fibrosis of liver tissues. Liver fibrosis is a condition that the balance between the synthesis and degradation procedures of a connective tissue is lost, caused by excessive accumulation of connective tissues within liver tissues, and accompanied by necrosis or inflammation. In particular, hepatic stellate cells (HSCs) that store vitamin A in normal liver are converted into myofibroblasts by acute and chronic liver damage, rapidly proliferate and synthesize an excessive amount of connective tissues through the increase in the synthesis and translocation of an extracellular matrix such as collagen, proteoglycan or hyaluronan, which results in stimulating the progression of liver fibrosis [Friedman et al., Proc. Natl. Acad. Sci. USA., 82: 8681 (1985) Gressner et al., Biochem. Biophys. Res. Commun., 151: 222 (1988) Gressner et al., J. Hepatol., 22: 28 (1995)]. In such procedure, TGF-β is synthesized, secreted and activated by several kinds of cells in the liver tissues, in particular, Kupffer cells or hepatic stellate cells activated by TGF-β, induce the proliferation and development of hepatic stellate cells, and thereby, play an important role in inducing the over-production and accumulation of an extracellular matrix such as collagen. It has been reported that in chronic liver disease such as hepatic fibrosis or liver cirrhosis, TGF-β is only expressed in the liver tissues undergoing fibrosis, increases the amount of an extracellular matrix, and finally, stimulates the progression of hepatic fibrosis [Bauer and Schuppan, FEBS Lett. 502:1-3 (2001); Bedossa and Paradis, J Hepatol., 22 (Suppl. 2):37-4 (1995)].
Until now, the development of an inhibitor for hepatic fibrosis or a therapeutic agent for liver cirrhosis has been focused on the development of a drug which inhibits the over-production of a connective tissue (representatively, collagen) of hepatic stellate cells or inhibits the growth thereof, but it has not yet been developed as an effective therapeutic agent. Recently, studies have been actively conducted on the inhibition of TGF-β function or TGF-β receptor activation as a target for developing a new therapeutic agent for liver cirrhosis, based on the fact that TGF-β is the strongest inducible factor for fibrosis of hepatic stellate cells among cytokines involved in fibrosis.
The present inventors have therefore synthesized numerous compounds having antagonistic activity on TGF-β receptor, endeavored to screen a new compound capable of inhibiting or preventing hepatic fibrosis among them by employing hepatic stellate cells that play an important role in the progression of hepatic fibrosis, and finally, found that a benzopyran derivative having a novel structure shows significant prophylactic and therapeutic effect.